Association of synovial expression of growth and differentiation factor 5 (GDF5) with radiographic severity of knee osteoarthritis.

Objectives: The growth and differentiation factor 5 (GDF5) gene plays a significant role in facilitating chondrogenesis, and GDF5 polymorphism is a genetic factor contributing to osteoarthritis (OA). However, the role of GDF5 expression in the synovial membrane remains unclear. The aim of this study was to determine the expression of GDF5 in the synovium in patients with primary knee OA. Materials and methods: Thirty patients scheduled for total knee arthroplasty were enrolled. Patients were grouped according to the Kellgren and Lawrence classification (KL) as grade 3 (15 patients) and grade 4 (15 patients). Synovial tissue was collected, and the GDF5 expression level was determined by real-time PCR. Ten synovial samples were randomly selected to evaluate the degree of synovitis. Results: Baseline characteristics did not differ between the two groups. The expression of GDF5 was significantly higher in the KL4 group (median expression 3.50, range 1.45-13.62) than in the KL3 group (median expression 1.81, range 0-9.46) (p value = 0.02). Histological staining of the synovium indicated low-grade synovitis in both groups. Conclusions: GDF5 expression in the synovium was positively associated with the radiographic severity of knee OA. The difference in GDF5 expression between the KL3 and KL4 groups supports the hypothesis that, through GDF5, the synovium may have important roles in cartilage maintenance and homeostasis in primary knee OA.

Chitosan oligosaccharide suppresses synovial inflammation via AMPK activation: An in vitro and in vivo study.

Synovial inflammation plays an important role in the early pathogenesis of osteoarthritis (OA). Chitosan oligosaccharide (COS) has been shown to activate AMPK and suppress inflammatory responses in intestinal epithelial cells. This study aimed to investigate the effect of COS on AMPK activation and synovial inflammation using both primary cultures of synoviocytes and a rabbit model of anterior cruciate ligament (ACL) transection-induced OA. COS induced AMPK activation in both rabbit and human synoviocytes. The mechanism of COS-induced AMPK activation involves an increase in the ADP/ATP ratio but not calcium/calmodulin-dependent protein kinase kinase beta (CaMKKß). Interestingly, COS suppressed the TNFα-induced iNOS and COX-2 expression via an AMPK-dependent mechanism in both rabbit and human synoviocytes. Importantly, oral administration of COS (10mg/kg/day) induced AMPK activation and alleviated signs of inflammation including COX-2 expression in the synovium of a rabbit ACL transection model. Taken together, our results indicate that COS suppresses synovial inflammation in vitro and in vivo via AMPK activation. COS may be useful in the prevention of OA.

Positively selected G6PD-Mahidol mutation reduces Plasmodium vivax density in Southeast Asians.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency--the most common known enzymopathy--is associated with neonatal jaundice and hemolytic anemia usually after exposure to certain infections, foods, or medications. Although G6PD-deficient alleles appear to confer a protective effect against malaria, the link with clinical protection from Plasmodium infection remains unclear. We investigated the effect of a common G6PD deficiency variant in Southeast Asia--the G6PD-Mahidol(487A) variant--on human survival related to vivax and falciparum malaria. Our results show that strong and recent positive selection has targeted the Mahidol variant over the past 1500 years. We found that the G6PD-Mahidol(487A) variant reduces vivax, but not falciparum, parasite density in humans, which indicates that Plasmodium vivax has been a driving force behind the strong selective advantage conferred by this mutation.

Heritability of P. falciparum and P. vivax malaria in a Karen population in Thailand.

The majority of studies concerning malaria host genetics have focused on individual genes that confer protection against rather than susceptibility to malaria. Establishing the relative impact of genetic versus non-genetic factors on malaria infection and disease is essential to focus effort on key determinant factors. This relative contribution has rarely been evaluated for Plasmodium falciparum and almost never for Plasmodium vivax. We conducted a longitudinal cohort study in a Karen population of 3,484 individuals in a region of mesoendemic malaria, Thailand from 1998 to 2005. The number of P. falciparum and P. vivax clinical cases and the parasite density per person were determined. Statistical analyses were performed to account for the influence of environmental factors and the genetic heritability of the phenotypes was calculated using the pedigree-based variance components model. The genetic contribution to the number of clinical episodes resulting from P. falciparum and P. vivax were 10% and 19% respectively. There was also moderate genetic contribution to the maximum and overall parasite trophozoite density phenotypes for both P. falciparum (16%&16%) and P. vivax (15%&13%). These values, for P. falciparum, were similar to those previously observed in a region of much higher transmission intensity in Senegal, West Africa. Although environmental factors play an important role in acquiring an infection, genetics plays a determinant role in the outcome of an infection with either malaria parasite species prior to the development of immunity.